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Polymorphic antiviral nucleoside compounds

a nucleoside compound and polymorphic technology, applied in the direction of biocide, drug composition, peptide/protein ingredients, etc., can solve the problem that their clinical utility is often hampered

Inactive Publication Date: 2005-06-16
ROCHE PALO ALTO LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While nucleoside derivatives frequently possess high levels of biological activity, their clinical utility is often hampered by suboptimal physical properties and limited bioavailability requiring large doses at frequent intervals to maintain therapeutically effective levels.
These salt forming agents, however, must be identified empirically by the pharmaceutical chemist since there is no reliable method to predict the influence of a salt species on the behavior of a parent compound in dosage forms.
These oft conflicting requirements make identification suitable salts a challenging and important problem which must be solved by the skilled pharmaceutical scientist before drug development can proceed in earnest.

Method used

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  • Polymorphic antiviral nucleoside compounds
  • Polymorphic antiviral nucleoside compounds
  • Polymorphic antiviral nucleoside compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

Form A Polymorph

[0074] Levovirin valinate hydrochloride (Ib; 75 gm) was warmed to 65° C. in 1.2 L of iso-propanol, and 85 mL of water to produce a homogenous solution This solution was slowly cooled to room temperature and the resulting slurry was filtered, washed with iso-propanol and dried to yield 71 g of the Form A polymorph (m.p. 163-165° C.). (Optionally 4.5 mL of 37% hydrochloric acid can be added to the aqueous iso-propanol solution).

example 2

Form B Polymorph

[0075] Levovirin valinate hydrochloride (Ib; 2.8 g) was dissolved in 4 mL of water (saturated solution) and cooled to 2 to 4° C. or lower. After at least three days crystalline plates were recovered by filtration, washed with cold water and dried in vacuo to yield ˜2 g of Form B polymorph (m.p. 144° C.; decomposition).

example 3

Bulk and Tap Density

[0076] The bulk density of Ib was determined Vanderkamp™ tap density tester, with an acoustic cabinet, or equivalent (Van-Kel Industries, Inc., 36 Meridian Road, Edison, N.J. 08820) apparatus following. Ib was passed through a 20 mesh. A powder funnel was placed on top of a cylinder and the powder was transferred rapidly in to the cylinder while avoiding agitation or tapping of the cylinder and the lower funnel. The sample weight in the cylinder was determined and the bulk density was calculated.

[0077] The tapped density was determined by measuring the volume of drug substance in a 25 mL graduated cylinder after 300 taps of a known amount of drug substance. The apparatus used was a VanderKamp Tapped Density Tester. The tapped density was calculated as the known weight of drug substance divided by the measured volume.

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Abstract

The present invention relates to the polymorphic crystalline hydrochloride salts of a nucleoside valinate ester according to formula Ib, methods of treating diseases mediated by Hepatitis C Virus and pharmaceutical composition containing Ib.

Description

CROSS REFERENCE TO PRIOR APPLICATION [0001] This application claims benefit under Title 35 U.S.C. 119(e) of U.S. Provisional Application No. 60 / 502,105, filed Sep. 11, 2003, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] The present invention relates to polymorphic crystalline forms of 2-(S)-amino-3-methyl-butyric acid 5S-(3-carbamoyl-[1,2,4]triazol-1-yl)-3R,4S-dihydroxy-tetrahydrofuran-2S-yl methyl ester, monohydrochloride (Ib) with improved stability and physical properties which facilitate manufacturing, handling and formulating I. BACKGROUND OF THE INVENTION [0003] Hepatitis C virus (HCV) is responsible for a large proportion of the chronic liver disease worldwide and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global proportion of hepatitis C is estimated to average 3% (ranging from 0.1% to 5.0%); there are an estimated 170 million chronic carriers throughout the world. There is a continuing need for e...

Claims

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Application Information

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IPC IPC(8): A61K31/7056A61K38/21C07H19/056
CPCC07H19/056A61P1/16A61P31/12
Inventor BIRUDARAJ, KONDAMRAJPRINCE, ANTHONYMCCARTHY, KEITH
Owner ROCHE PALO ALTO LLC